Alcohol Consumption & Cancer Risk

Alcohol Consumption & Cancer Risk
Full Title: Alcohol Consumption and Cancer Risk: Understanding the Possible Causal Mechanisms Explaining the Increased Risk of Breast and Colorectal Cancer with Alcohol Consumption
Evidence-based Practice Center Systematic Review Protocol
Expected Release Date: late 2010

Contents
Background
Scope
Key Questions
Analytic Framework
Objective
Disposition of the Documents Identified by Literature Searches
Methods
References
Summary of Protocol Amendments
Appendix 1



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Background

Alcohol consumption is highly prevalent in the general U.S. population. The 2008 prevalence and trends data from the Behavioral Risk Factor Surveillance System indicated that about 54% of U.S. adults had consumed alcohol within the past 30 days.1 Though moderate alcohol consumption may have some potential health benefits, worldwide, alcohol consumption has been identified as one of the major risks for increasing the burden of disease.2 Several epidemiologic studies have reported moderate to strong associations between the level of alcohol consumption and the incidence of cancers of the mouth, pharynx, larynx, esophagus, and liver.3-7 Observed associations of alcohol consumption and cancer, however, can be confounded by other risk factors for cancer, such as age, smoking, family history, physical condition, and race or ethnicity.8-11

Although the association between alcohol and breast and colorectal cancer is comparatively less strong than the association with the cancers named above, given the high prevalence and incidence of breast and colorectal cancer, reducing the effect of any contributing factor may have a large overall impact on cancer incidence and prevalence.4-6,8,12-17 Because of the high prevalence of alcohol consumption, exploring the potential underlying mechanism(s) of the association between alcohol consumption and breast and colorectal cancers is essential in developing primary preventive measures. Since alcohol consumption is a modifiable behavior,18 recommending and promoting changes in behavior and appropriate preventive interventions may help reduce cancer risks in the general population.



Scope
The purpose of this report is to systematically and objectively synthesize evidence from the basic science literature to clarify the possible causal mechanisms by which alcohol could contribute to cancer risk, focusing on breast cancer and colorectal cancer. Although an integration of typical epidemiological studies with more basic biological literature has value, the scope of this project is confined to potential pathophysiological/toxicological mechanisms of action and not on the societal determinants of drinking alcohol. Epidemiological data, however, may provide insight into the dose/response relationship.

Apart from alcohol and water, the exact composition of most drinks on the market remains confidential and is not available to the general public.18 Therefore, the scope of this report is limited to ethanol. Other compounds (or contaminants) found in various alcoholic beverages that may play a role in the development of breast and colorectal cancers are outside the scope of this report. These compounds include nitrosamines, aflatoxins, polyphenols, ethyl carbamate (urethane), asbestos, and arsenic compounds, and more.3,16,19,20



Key Questions
1. What are the likely causal mechanisms by which alcohol contributes to the development of breast cancer? Which of the possible mechanisms (e.g., induction of p450 cytochromes and carcinogen metabolism, effects on blood hormone concentrations, effect of acetaldehyde or other alcohol metabolite on apoptosis and DNA repair, interactive effects on other nutritional factors, or others) are likely to be most important in breast cancer development?

2. For the most likely mechanisms of action involving alcohol and the development of breast cancer, how might other factors modify the effect of alcohol on breast cancer (for example, age, latency of effect, intensity, duration, and recency of exposure, presence of co-carcinogens, presence of threshold effect)? Do the causal mechanisms vary by cell type or other tumor characteristics?

3. What are the likely causal mechanisms by which alcohol contributes to the development of colorectal cancer? Which of the possible mechanisms (e.g., induction of p450 cytochromes and carcinogen metabolism, effects on blood hormone concentrations, effect of acetaldehyde or other alcohol metabolite on apoptosis and DNA repair, interactive effects on other nutritional factors, or others) are likely to be most important in colorectal cancer development?

4. For the most likely mechanisms of action involving alcohol and the development of colorectal cancer, how might other factors modify the effect of alcohol on colorectal cancer (for example, age, latency of effect, intensity, duration, and recency of exposure, presence of co-carcinogens, presence of threshold effect)? Do the causal mechanisms vary by cell type or other tumor characteristics?


Analytic Framework
Figures 1 and 2 are analytic frameworks that diagram the linkage between alcohol and cancer induction of either breast or colorectal cancer in humans or animals. The linkage between alcohol and cancer induction is through either risk factors related to alcohol (KQ 2 for breast cancer and KQ4 for colon cancer) or through alcohol metabolites (KQ1 for breast cancer and KQ3 for colorectal cancer). The mechanism of the relationship is to be examined within studies of human or animal isolated organs and cells, which may include studies of whole humans or animals or through studies on cell lines.



Alcohol Consumption & Cancer Risk
Figure 1: Analytical Framework for Breast Cancer (Text Description)
The Analytical Framework begins with two text boxes captioned "Whole Human or Whole Animal" and "Cell lines." Arrows point from these two boxes to a third box captioned "Human or Animal Isolated Organs and Cells"; an arrow points from this box to another captioned "Alcohol."

Three arrows point away from "Alcohol." The uppermost of these is a broken grey line, pointing to a box that reads "Other Risk Factors" and captioned KQ (Key Question) 2. The middle arrow is also a broken grey line, pointing to a box that reads "Cancer induction." The lowest arrow is a solid black line, pointing to a box that reads "Alcohol metabolites" and captioned KQ 1. Broken grey line ending in arrows also point from "Other Risk Factors" and "Alcohol metabolites" to "Cancer induction."

An arrow with a solid black line points away from "Cancer induction" to an ovoid captioned "Breast Cancer."



Alcohol Consumption & Cancer Risk
Figure 2: Analytical Framework for Colorectal Cancer (Text Description)
The Analytical Framework begins with two text boxes captioned "Whole Human or Whole Animal" and "Cell lines." Arrows point from these two boxes to a third box captioned "Human or Animal Isolated Organs and Cells"; an arrow points from this box to another captioned "Alcohol."

Three arrows point away from "Alcohol." The uppermost of these is a broken grey line, pointing to a box that reads "Other Risk Factors" and captioned KQ (Key Question) 4. The middle arrow is also a broken grey line, pointing to a box that reads "Cancer induction." The lowest arrow is a solid black line, pointing to a box that reads "Alcohol metabolites" and captioned KQ 3. Broken grey line ending in arrows also point from "Other Risk Factors" and "Alcohol metabolites" to "Cancer induction."

An arrow with a solid black line points away from "Cancer induction" to an ovoid captioned "Colorectal Cancer."





Objective
The purpose of our assessment is not to determine the exact extent to which alcohol is a risk factor for breast and colorectal cancers, but instead to explore the possible underlying causal mechanism(s) of the association between alcohol consumption and breast and colorectal cancers (see broken arrows from alcohol to cancer induction in analytical framework above).


Disposition of the Documents Identified by Literature Searches
Figure 3 is a flow chart depicting the pathway by which identified documents may be excluded at various levels, including the abstract or full document level, before being included in the report. Of those documents included in the report, some may be included in background or future research sections, such as those describing mechanisms of basic cancer, breast cancer, or colorectal cancer, alcohol metabolism, epidemiology of alcohol or cancer, or other components of alcoholic drinks. The remaining documents that would be included in the evidence base would be comprised of human studies with tissue/biochemical/histopathology analysis, whole animal models, animal tissue, human cell lines, non-human cell lines.




Alcohol Consumption & Cancer Risk
Figure 3: Flow chart depicting the pathway by which identified documents may be excluded at various levels (Text Description)
The flow chart begins with "Documents identified"; an arrow points down to a rhombus labeled "Abstracts Screened." Two arrows point from "Abstracts Screened," one to "Documents excluded at the abstract level" and the other to "Full documents retrieved."

An arrow points down from "Full documents retrieved" to a rhombus labeled "Full documents reviewed." Two arrows point from "Full documents reviewed," one to "Documents excluded at the full document level" and the other to "Documents to be included in the report."

An arrow points down from "Documents to be included in the report" to a rhombus labeled "Full documents reviewed for inclusion in the evidence base." Two arrows point from "Full documents reviewed," one to "Documents to be included in the background or future research sections of the report: Basic cancer mechanisms; Breast cancer mechanisms; Colorectal cancer mechanisms; Alcohol metabolism; Epidemiology studies of alcohol and cancer; Other components of alcoholic drinks." The other arrow points down to "Studies addressing the key questions; this constitutes the evidence base of the report: Human studies with tissue/biochemical/histopathology analysis; Whole animal models; Animal tissue; Human cell lines; Non-human cell lines."



Study Selection
We will use the following formal criteria to determine which studies will be included in our analysis.

Any study, regardless of design, that provides data on the possible causal mechanism(s) of any association between alcohol consumption and breast and colorectal cancers in any population setting, including humans, animals and in vitro experimental studies.


Methods
Given that this report will be examining proposed hypotheses rather than testing them, we will be providing an overview of the evidence on physiological and biochemical mechanisms by categorizing and synthesizing information on identified causal mechanisms in order to determine which mechanisms have the most supporting evidence.

The members of the Technical Expert Panel (TEP) proposed several methods for evaluating studies using animals, tissues, or cells as the primary experimental model.

^ Evidence from interventional studies offer the most compelling evidence that a mechanism/pathway is directly involved in increasing cancer risk with alcohol intake.
º Interventional studies that directly interfere with a pathway or mechanism suspected of linking alcohol intake to an increase in cancer risk will be considered of higher internal validity than observational studies describing an association between alcohol intake and cancer. An interventional study would test the hypothesis that alcohol intake would increase cancer risk when a particular pathway is intact, but not when the pathway is blocked.
^ Use of alcohol concentration levels in animal studies that far exceed levels that occur in humans will be considered of low applicability.
^ Cell lines should be appropriate to the study of breast and colorectal cancer in humans.
^ The use of carcinogens, co-carcinogens, and other agents should be appropriate to the study of breast and colorectal cancer in humans.


References
1. Prevalence and trends data. Nationwide (states, DC, and territories) [internet]. Altanta (GA): Centers for Disease Control and Prevention (CDC); 2008. [accessed 2009 Aug 21]. 2008 alcohol consumption: adults who have had at least one drink of alcohol within the past 30 days. [2 p]. Available: http://apps.nccd.cdc.gov/brfss/index.asp.

2. WHO. Global status report on alcohol 2004. Geneva: World Health Organization (WHO); 2004. 94 p.

3. Baan R, Straif K, Grosse Y, Secretan B, El Ghissassi F, Bouvard V, Altieri A, Cogliano V, WHO International Agency for Research on Cancer Monograph Working Group. Carcinogenicity of alcoholic beverages. Lancet Oncol 2007 Apr;8(4):292-3. PMID: 17431955

4. Poschl G, Seitz HK. Alcohol and cancer. Alcohol Alcohol 2004 May-Jun;39(3):155-65. PMID: 15082451

5. Giovannucci E. Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. J Nutr 2004 Sep;134(9):2475S-81S. PMID: 15333745

6. Hamajima N, Hirose K, Tajima K, Rohan T, Calle EE, Heath CW Jr, Coates RJ, Liff JM, Talamini R, Chantarakul N, Koetsawang S, Rachawat D, Morabia A, Schuman L, Stewart W, Szklo M, Bain C, Schofield F, Siskind V, Band P, Coldman AJ, Gallagher RP, Hislop TG, Yang P, Kolonel LM, Nomura AM, Hu J, Johnson. Alcohol, tobacco and breast cancer—collaborative reanalysis of individual data from 53 epidemiological studies, including 58,515 women with breast cancer and 95,067 women without the disease. Br J Cancer 2002 Nov 18;87(11):1234-45. PMID: 12439712

7. O'Hanlon LH. Studies seek molecular clues on alcohol's role in cancer. J Natl Cancer Inst 2005 Nov 2;97(21):1563-4. PMID: 16264173

8. Cho E, Smith-Warner SA, Ritz J, van den Brandt PA, Colditz GA, Folsom AR, Freudenheim JL, Giovannucci E, Goldbohm RA, Graham S, Holmberg L, Kim DH, Malila N, Miller AB, Pietinen P, Rohan TE, Sellers TA, Speizer FE, Willett WC, Wolk A, Hunter DJ. Alcohol intake and colorectal cancer: a pooled analysis of 8 cohort studies. Ann Intern Med 2004 Apr 20;140(8):603-13. PMID: 15096331

9. Key TJ, Schatzkin A, Willett WC, Allen NE, Spencer EA, Travis RC. Diet, nutrition and the prevention of cancer. Public Health Nutr 2004 Feb;7(1A):187-200. PMID: 14972060

10. Schatzkin A, Longnecker MP. Alcohol and breast cancer. Where are we now and where do we go from here? Cancer 1994 Aug 1;74(3 Suppl):1101-10. PMID: 8039145

11. Seitz HK, Stickel F. Molecular mechanisms of alcohol-mediated carcinogenesis. Nat Rev Cancer 2007 Aug;7(8):599-612. PMID: 17646865

12. Zhang Y, Kreger BE, Dorgan JF, Splansky GL, Cupples LA, Ellison RC. Alcohol consumption and risk of breast cancer: the Framingham Study revisited. Am J Epidemiol 1999 Jan 15;149(2):93-101. PMID: 9921953

13. Feigelson HS, Jonas CR, Robertson AS, McCullough ML, Thun MJ, Calle EE. Alcohol, folate, methionine, and risk of incident breast cancer in the American Cancer Society Cancer Prevention Study II Nutrition Cohort. Cancer Epidemiol Biomarkers Prev 2003 Feb;12(2):161-4. PMID: 12582027

14. Smith-Warner SA, Spiegelman D, Yaun SS, van den Brandt PA, Folsom AR, Goldbohm RA, Graham S, Holmberg L, Howe GR, Marshall JR, Miller AB, Potter JD, Speizer FE, Willett WC, Wolk A, Hunter DJ. Alcohol and breast cancer in women: a pooled analysis of cohort studies. JAMA 1998 Feb 18;279(7):535-40. PMID: 9480365

15. Purohit V, Khalsa J, Serrano J. Mechanisms of alcohol-associated cancers: introduction and summary of the symposium. Alcohol 2005 Apr;35(3):155-60. PMID: 16054976

16. Seitz HK, Simanowski UA. Alcohol and carcinogenesis. Annu Rev Nutr 1988;8:99-119. PMID: 3060182

17. Singletary K. Ethanol and experimental breast cancer: a review. Alcohol Clin Exp Res 1997 Apr;21(2):334-9. PMID: 9113272

18. Lilla C, Koehler T, Kropp S, Wang-Gohrke S, Chang-Claude J. Alcohol dehydrogenase 1B (ADH1B) genotype, alcohol consumption and breast cancer risk by age 50 years in a German case-control study. Br J Cancer 2005 Jun 6;92(11):2039-41. PMID: 15886702

19. US Department of Health and Human Services, Public Health Service, National Toxicology Program. Alcoholic beverage consumption. Known to be a human carcinogen. Rockville (MD): U.S. Department of Health and Human Services; 2000. 2 p.

20. Monteiro R, Calhau C, Silva AO, Pinheiro-Silva S, Guerreiro S, Gartner F, Azevedo I, Soares R. Xanthohumol inhibits inflammatory factor production and angiogenesis in breast cancer xenografts. J Cell Biochem 2008 Aug 1;104(5):1699-707. PMID: 18348194



Summary of Protocol Amendments
In the event of protocol amendments, the date of each amendment will be accompanied by a description of the change and the rationale.

Note: The following protocol elements are standard procedures for all protocols.

Review of Key Questions
For Comparative Effectiveness reviews the key questions were posted for public comment and finalized after review of the comments. For other systematic reviews, key questions submitted by partners are reviewed and refined as needed by the EPC and the Technical Expert Panel (TEP) to assure that the questions are specific and explicit about what information is being reviewed.

Technical Expert Panel (TEP)
A TEP panel is selected to provide broad expertise and perspectives specific to the topic under development. Divergent and conflicted opinions are common and perceived as health scientific discourse that results in a thoughtful, relevant systematic review. Therefore study questions, design and/or methodological approaches do not necessarily represent the views of individual technical and content experts. The TEP provides information to the EPC to identify literature search strategies, review the draft report and recommend approaches to specific issues as requested by the EPC. The TEP does not do analysis of any kind nor contribute to the writing of the report.

Peer Review (Standard Language)
Approximately five experts in the field will be asked to peer review the draft report and provide comments. The peer reviewer may represent stakeholder groups such as professional or advocacy organizations with knowledge of the topic. On some specific reports such as reports requested by the Office of Medical Applications of Research, National Institutes of Health there may be other rules that apply regarding participation in the peer review process. Peer review comments on the preliminary draft of the report are considered by the EPC in preparation of the final draft of the report. The synthesis of the scientific literature presented in the final report does not necessarily represent the views of individual reviewers. The dispositions of the peer review comments are documented and will, for Comparative Effectiveness Reviews (CERs) and Technical Briefs, be published three months after the publication of the Evidence Report.

It is our policy not to release the names of the peer reviewers or TEP panel members until the report is published so that they can maintain their objectivity during the review process.


Evidence-based Practice Center: ECRI Institute

Current as of March 2010


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Internet Citation:

Alcohol Consumption and Cancer Risk, Review Protocol. March 2010. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/tp/alccantp.htm
http://www.ahrq.gov/clinic/tp/alccantp.htm